Skip to main content

White matter and cerebellar involvement in alternating hemiplegia of childhood

Journal of Neurology volume 267, pages 1300–1311 (2020)Cite this article

Abstract

Objective

To determine whether brain volumetric and white matter microstructural changes are present and correlate with neurological impairment in subjects with alternating hemiplegia of childhood (AHC).

Methods

In this prospective single-center study, 12 AHC subjects (mean age 22.9 years) and 24 controls were studied with 3DT1-weighted MR imaging and high angular resolution diffusion imaging at 3T. Data obtained with voxel-based morphometry and tract-based spatial statistics were correlated with motor impairment using the International Cooperative Ataxia Rating Scale (ICARS) and Movement and Disability sub-scales of Burke-Fahn-Marsden Dystonia Rating Scale (BFMMS and BFMDS).

Results

Compared to healthy controls, AHC subjects showed lower total brain volume (P < 0.001) and white matter volume (P = 0.002), with reduced clusters of white matter in frontal and parietal regions (P < 0.001). No significant regional differences were found in cortical or subcortical grey matter volumes. Lower cerebellar subvolumes correlated with worse ataxic symptoms and global motor impairment in AHC group (P < 0.001). Increased mean and radial diffusivity values were found in the corpus callosum, corticospinal tracts, superior and inferior longitudinal fasciculi, subcortical frontotemporal white matter, internal and external capsules, and optic radiations (P < 0.001). These diffusion scalar changes correlated with higher ICARS and BFMDS scores (P < 0.001).

Interpretation

AHC subjects showed prevalent white matter involvement, with reduced volume in several cerebral and cerebellar regions associated with widespread microstructural changes reflecting secondary myelin injury rather than axonal loss. Conversely, no specific pattern of grey matter atrophy emerged. Lower cerebellar volumes, correlating with severity of neurological manifestations, seems related to disrupted developmental rather than neurodegenerative processes.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

USD 39.95

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Abbreviations

AD:

Axial diffusivity

AHC:

Alternating hemiplegia of childhood

BFMDS:

Disability subscale of the Burke–Fahn–Marsden Dystonia Rating Scale

BFMMS:

Movement subscale of the Burke–Fahn–Marsden Dystonia Rating Scale

CSF:

Cerebrospinal fluid

DTI:

Diffusion tensor imaging

FA:

Fractional anisotropy

GLM:

General linear model

ICARS:

International Cooperative Ataxia Rating Scale

MD:

Mean diffusivity

MNI:

Montreal neurological institute

RD:

Radial diffusivity

TBSS:

Tract-based spatial statistics

VBM:

Voxel-based morphometry

WM:

White matter

References

  1. Verret S, Steele JC (1971) Alternating hemiplegia in childhood: a report of eight patients with complicated migraine beginning in infancy. Pediatrics 47:675–680

    CAS  PubMed  Google Scholar 

  2. Sweney MT, Silver K, Gerard-Blanluet M et al (2009) Alternating hemiplegia of childhood: early characteristics and evolution of a neurodevelopmental syndrome. Pediatrics 123:e534–e541. https://doi.org/10.1542/peds.2008-2027

    Article  PubMed  Google Scholar 

  3. Heinzen EL, Swoboda KJ, Hitomi Y et al (2012) De novo mutations in ATP1A3 cause alternating hemiplegia of childhood. Nat Genet 44:1030–1034. https://doi.org/10.1038/ng.2358

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Rosewich H, Thiele H, Ohlenbusch A et al (2012) Heterozygous de-novo mutations in ATP1A3 in patients with alternating hemiplegia of childhood: a whole-exome sequencing gene-identification study. Lancet Neurol 11:764–773. https://doi.org/10.1016/S1474-4422(12)70182-5

    Article  CAS  PubMed  Google Scholar 

  5. Panagiotakaki E, Gobbi G, Neville B et al (2010) Evidence of a non-progressive course of alternating hemiplegia of childhood: study of a large cohort of children and adults. Brain 133:3598–3610. https://doi.org/10.1093/brain/awq295

    Article  PubMed  Google Scholar 

  6. Saito Y, Sakuragawa N, Sasaki M et al (1998) A case of alternating hemiplegia of childhood with cerebellar atrophy. Pediatr Neurol 19:65–68

    Article  CAS  Google Scholar 

  7. Saito Y, Inui T, Sakakibara T et al (2010) Evolution of hemiplegic attacks and epileptic seizures in alternating hemiplegia of childhood. Epilepsy Res 90:248–258. https://doi.org/10.1016/j.eplepsyres.2010.05.013

    Article  PubMed  Google Scholar 

  8. Sasaki M, Ishii A, Saito Y, Hirose S (2017) Progressive brain atrophy in alternating hemiplegia of childhood. Mov Disord Clin Pract 4:406–411. https://doi.org/10.1002/mdc3.12451

    Article  PubMed  PubMed Central  Google Scholar 

  9. Pavlidis E, Uldall P, Gøbel Madsen C et al (2017) Alternating hemiplegia of childhood and a pathogenic variant of ATP1A3: a case report and pathophysiological considerations. Epileptic Disord 19:226–230. https://doi.org/10.1684/epd.2017.0913

    Article  PubMed  Google Scholar 

  10. Giacanelli M, Petrucci A, Lispi L et al (2017) ATP1A3 mutant patient with alternating hemiplegia of childhood and brain spectroscopic abnormalities. J Neurol Sci 379:36–38. https://doi.org/10.1016/j.jns.2017.05.041

    Article  CAS  PubMed  Google Scholar 

  11. Shanmugarajah PD, Hoggard N, Aeschlimann DP et al (2018) Phenytoin-related ataxia in patients with epilepsy: clinical and radiological characteristics. Seizure 56:26–30. https://doi.org/10.1016/j.seizure.2018.01.019

    Article  PubMed  Google Scholar 

  12. Mendes A, Sampaio L (2016) Brain magnetic resonance in status epilepticus: a focused review. Seizure 38:63–67. https://doi.org/10.1016/j.seizure.2016.04.007

    Article  PubMed  Google Scholar 

  13. Trouillas P, Takayanagi T, Hallett M et al (1997) International cooperative ataxia rating scale for pharmacological assessment of the cerebellar syndrome. The ataxia neuropharmacology committee of the world federation of neurology. J Neurol Sci 145:205–211

    Article  CAS  Google Scholar 

  14. Burke RE, Fahn S, Marsden CD et al (1985) Validity and reliability of a rating scale for the primary torsion dystonias. Neurology 35:73–77

    Article  CAS  Google Scholar 

  15. Good CD, Johnsrude IS, Ashburner J et al (2001) A voxel-based morphometric study of ageing in 465 normal adult human brains. Neuroimage 14:21–36. https://doi.org/10.1006/nimg.2001.0786

    Article  CAS  PubMed  Google Scholar 

  16. Smith SM, Jenkinson M, Johansen-Berg H et al (2006) Tract-based spatial statistics: voxelwise analysis of multi-subject diffusion data. Neuroimage 31:1487–1505. https://doi.org/10.1016/j.neuroimage.2006.02.024

    Article  PubMed  Google Scholar 

  17. Mori S, Oishi K, Faria AV (2009) White matter atlases based on diffusion tensor imaging. Curr Opin Neurol 22:362–369. https://doi.org/10.1097/WCO.0b013e32832d954b

    Article  PubMed  PubMed Central  Google Scholar 

  18. Toselli B, Tortora D, Severino M et al (2017) Improvement in white matter tract reconstruction with constrained spherical deconvolution and track density mapping in low angular resolution data: a pediatric study and literature review. Front Pediatr. https://doi.org/10.3389/fped.2017.00182

    Article  PubMed  PubMed Central  Google Scholar 

  19. Winkler AM, Ridgway GR, Webster MA et al (2014) Permutation inference for the general linear model. Neuroimage 92:381–397. https://doi.org/10.1016/J.NEUROIMAGE.2014.01.060

    Article  PubMed  PubMed Central  Google Scholar 

  20. Pisciotta L, Gherzi M, Stagnaro M et al (2017) Alternating hemiplegia of childhood: pharmacological treatment of 30 Italian patients. Brain Dev 39:521–528. https://doi.org/10.1016/j.braindev.2017.02.001

    Article  PubMed  Google Scholar 

  21. Diedrichsen J, Zotow E (2015) Surface-based display of volume-averaged cerebellar imaging data. PLoS ONE 10:e0133402. https://doi.org/10.1371/journal.pone.0133402

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Diedrichsen J, Balsters JH, Flavell J et al (2009) A probabilistic MR atlas of the human cerebellum. Neuroimage 46:39–46. https://doi.org/10.1016/j.neuroimage.2009.01.045

    Article  PubMed  Google Scholar 

  23. Oblak AL, Hagen MC, Sweadner KJ et al (2014) Rapid-onset dystonia-parkinsonism associated with the I758S mutation of the ATP1A3 gene: a neuropathologic and neuroanatomical study of four siblings. Acta Neuropathol 128:81–98. https://doi.org/10.1007/s00401-014-1279-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Ikeda K, Onimaru H, Kawakami K (2017) Knockout of sodium pump α3 subunit gene (Atp1a3 −/− ) results in perinatal seizure and defective respiratory rhythm generation. Brain Res 1666:27–37. https://doi.org/10.1016/j.brainres.2017.04.014

    Article  CAS  PubMed  Google Scholar 

  25. Ikeda K, Satake S, Onaka T et al (2013) Enhanced inhibitory neurotransmission in the cerebellar cortex of Atp1a3 -deficient heterozygous mice. J Physiol 591:3433–3449. https://doi.org/10.1113/jphysiol.2012.247817

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Severino M, Lualdi S, Fiorillo C et al (2018) Unusual white matter involvement in EAST syndrome associated with novel KCNJ10 mutations. J Neurol. https://doi.org/10.1007/s00415-018-8826-7

    Article  PubMed  Google Scholar 

  27. Bertini E, Zanni G, Boltshauser E (2018) Nonprogressive congenital ataxias. In: Handbook of clinical neurology. Elsevier, Amsterdam, pp 91–103

    Chapter  Google Scholar 

  28. Boltshauser E (2004) Cerebellum-small brain but large confusion: a review of selected cerebellar malformations and disruptions. Am J Med Genet A 126A:376–385. https://doi.org/10.1002/ajmg.a.20662

    Article  PubMed  Google Scholar 

  29. Burzynska AZ, Preuschhof C, Bäckman L et al (2010) Age-related differences in white matter microstructure: region-specific patterns of diffusivity. Neuroimage 49:2104–2112. https://doi.org/10.1016/j.neuroimage.2009.09.041

    Article  CAS  PubMed  Google Scholar 

  30. Chong CD, Schwedt TJ (2015) Migraine affects white-matter tract integrity: a diffusion-tensor imaging study. Cephalalgia 35:1162–1171. https://doi.org/10.1177/0333102415573513

    Article  PubMed  Google Scholar 

  31. Whitlow CT, Brashear A, Ghetti B, Hagen MC, Sweadner KJ, Maldjian JA (2012) Structural abnormalities in the brain associated with rapid onset dystonia-parkinsonism: a preliminary investigation. 2012 annual meeting, sunday, October 7, 2012 poster session abstracts. Ann Neurol 72:S1–S120. https://doi.org/10.1002/ana.23769

    Article  Google Scholar 

  32. Tan AH, Ong TL, Ramli N et al (2019) Alternating hemiplegia of childhood in a person of malay ethnicity with diffusion tensor imaging abnormalities. J Mov Disord 12:132–134. https://doi.org/10.14802/jmd.18063

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We are grateful to the members of the Italian AHC Family Association AISEA for participating in this study. This work was supported by funds from “Ricerca Corrente sui Disordini Neurologici e Muscolari (Linea 5)” of the Italian Ministry of Health. The IBAHC Consortium: Members of the IBAHC (Italian Biobank and Clinical Registry for Alternating Hemiplegia) Consortium and Working Group: 1. Maria Teresa Bassi, IRCCS Eugenio Medea, Bosisio Parini, Lecco, Italia; 2. Claudio Zucca, IRCCS Eugenio Medea, Bosisio Parini, Lecco, Italia; 3. Edvige Veneselli, IRCCS Istituto Giannina Gaslini, University of Genoa, Genova, Italia; 4. Filippo Franchini, AISEA (associazione italiana sindrome dell’emiplegia alternante) Onlus, Milano, Italia; 5. Maria Rosaria Vavassori, IAHCRC (International Consortium for the Research on Alternating Hemiplegia of Childhood) Consortium; 6. Melania Giannotta, IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italia; 7. Giuseppe Gobbi, IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italia; 8. Tiziana Granata, IRCCS Foundation Neurological Institute Carlo Besta, Milano, Italia; 9. Nardo Nardocci, IRCCS Foundation Neurological Institute Carlo Besta, Milano, Italia; 10. Francesca Ragona, IRCCS Foundation Neurological Institute Carlo Besta, Milano, Italia; 11. Fiorella Gurrieri, Servizio di Genetica Medica, Fondazione Policlinico Universitario IRCCS Agostino Gemelli, Istituto di Medicina Genomica Università Cattolica del S. Cuore, Rome, Italia; 12. Giovanni Neri, Servizio di Genetica Medica, Fondazione Policlinico Universitario IRCCS Agostino Gemelli, Istituto di Medicina Genomica Università Cattolica del S. Cuore, Rome, Italia; 13. Francesco Danilo Tiziano, Servizio di Genetica Medica, Fondazione Policlinico Universitario IRCCS Agostino Gemelli, Istituto di Medicina Genomica Università Cattolica del S. Cuore, Rome, Italia; 14. Federico Vigevano, Alessandro Capuano, Bambino Gesù Children's Hospital, IRCCS, Rome, Italia; 15. Stefano Sartori, Neurology and Neurophysiology Unit, Department of Women's and Children's Health, University Hospital of Padua, Padova, Italy

Author information

Author notes

  1. Mariasavina Severino and Livia Pisciotta equally contributed to this work.

Authors and Affiliations

  1. Neuroradiology Unit, IRCCS Istituto Giannina Gaslini, Genova, Italy

    Mariasavina Severino, Domenico Tortora, Giovanni Morana & Andrea Rossi

  2. Neuropsychiatry Unit, IRCCS Istituto Giannina Gaslini, via G. Gaslini 5, 16147, Genova, Italy

    Livia Pisciotta, Michela Stagnaro, Ramona Cordani & Elisa De Grandis

  3. Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), Università di Genova, Genova, Italy

    Livia Pisciotta, Ramona Cordani & Elisa De Grandis

  4. Department of Informatics, Bioengineering, Robotics and System Engineering, Università Degli Studi di Genova, Genova, Italy

    Benedetta Toselli

  5. Anesthesiology Unit, IRCCS Istituto Giannina Gaslini, Genova, Italy

    Anna Zicca, Svetlana Kotzeva, Clelia Zanaboni & Giovanni Montobbio

Authors
  1. Mariasavina Severino
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Livia Pisciotta
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Domenico Tortora
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Benedetta Toselli
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Michela Stagnaro
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ramona Cordani
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Giovanni Morana
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Anna Zicca
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Svetlana Kotzeva
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Clelia Zanaboni
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Giovanni Montobbio
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Andrea Rossi
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Elisa De Grandis
    View author publications

    You can also search for this author in PubMed Google Scholar

Consortia

the IBAHC Consortium

  • Maria Teresa Bassi
  • , Claudio Zucca
  • , Edvige Veneselli
  • , Filippo Franchini
  • , Maria Rosaria Vavassori
  • , Melania Giannotta
  • , Giuseppe Gobbi
  • , Tiziana Granata
  • , Nardo Nardocci
  • , Francesca Ragona
  • , Fiorella Gurrieri
  • , Giovanni Neri
  • , Francesco Danilo Tiziano
  • , Federico Vigevano
  • , Alessandro Capuano
  •  & Stefano Sartori

Contributions

MS, LP, EDG, The IBAHC Consortium participants: conception and design of the study; MS, LP, EDG, DT, BT, GM, MS, RC, AZ, SK, CZ: acquisition and analysis of data; MS, LP, EDG, DT, BT, GM, MS, RC, AZ, SK, CZ, GM, AR: drafting a significant portion of the manuscript or figures.

Corresponding author

Correspondence to Elisa De Grandis.

Ethics declarations

Conflicts of interest

The authors report no financial disclosure/conflict of interest concerning the research related to the manuscript.

Ethical standards

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants involved in the study.

Additional information

Members of the IBAHC Consortium and Working Group are listed in the acknowledgement section.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 46 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Severino, M., Pisciotta, L., Tortora, D. et al. White matter and cerebellar involvement in alternating hemiplegia of childhood. J Neurol 267, 1300–1311 (2020). https://doi.org/10.1007/s00415-020-09698-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00415-020-09698-3

Keywords

  • Alternating hemiplegia of childhood
  • Brain MRI
  • Voxel-based morphometry
  • Tract-based spatial statistics
  • White matter